Human cytomegalovirus (HCMV) is the most common congenital viral infection in humans with an incidence approaching 1% in live births in the United. States. HCMV is also the leading infectious cause of central nervous system (CNS) disease in the newborn period. Each year more than 6,000 infants suffer permanent CNS sequelae as a result of intrauterine infection. Natural history studies have shown that maternal HCMV specific seroimmunity prior to conception can markedly reduce the rate of intrauterine transmission and the severity of fetal infection, indicating that congenital HCMV infection is a vaccine modifiable disease. Studies in immunocompetent hosts indicate that virus neutralizing antibodies represent a major component of protective immunity and an prevent reinfection upon community exposure. Animal models of human diseases have confirmed these clinical studies. Recent studies in the guinea pig model of congenital HCMV infection have shown that immunization of female animals prior to conception with a single viral protein, the gB homolog of gpCMV, can limit the incidence and severity of fetal infection following maternal virus challenge during pregnancy. In this proposal we will directly explore the hypothesis that virus neutralizing antibodies represent a major protective response in women by comparing HCMV specific immunity in women immunized with a recombinant gB vaccine as part of a vaccine trial and women with naturally acquired, protective immunity. The effects of vaccine induced immunity on the level and duration of virus replication (viral burden) will be defined by characterizing the virological natural history of primary infection in vaccine recipients and placebo controls who become infected during the trial. We anticipate that our studies will provide a comprehensive understanding of the parameters of HCMV protective immunity in women of childbearing age and definition of the role of specific immune reactivity in the virological outcome of primary HCMV infection in this population. The goals of this project will provide essential information for interpretation of the results of the efficacy trial described in Project 1, complement the pathogenesis studies described in Project 3 by further defining protective maternal immunity, and further our understanding of host factors which may contribute to the increased risk of infection in young women which will be investigated in Project 4.